The Myb locus encodes the c-Myb transcription factor, which functions as both a transcription activator and repressor. c-Myb is absolutely required for definitive hematopoiesis and has been implicated in a variety of hematopoitic tumors including leukemia and lymphoma as well as solid tumors. In collaboration with Calabretta and colleagues, we recently demonstrated that loss of a single Myb allele severely reduces colony formation in bone marrow progenitors transduced with a p210BCR/ABL producing virus and extended survival in a model of CML blast crisis. This finding has been extended to transformation of B-lineage progenitors in two models of p190BCR/ABL-dependent B-cell leukemia (Waldron et al., manuscript submitted) and in this proposal we provide preliminary evidence that c-Myb is important for the continued survival and proliferation of Abl transformed pre-B cells. Thus, understanding what c-Myb does during normal hematopoiesis and identifying the downstream mediators of c-Myb activity is crucial for understanding c-Myb function during normal hematopoiesis and how c-Myb may function in cancer. However, gaining insight into c-Myb function has been difficult due to the embryonic lethality of null Myb mutations. We have produced mice that carry a loxP targeted Myb locus for conditional deletion by Cre recombinase. We have used these mice to define critical points during B cell development where c-Myb is required. c-Myb is required for the development, proliferation and survival of pro-B cells, transition from the pro-B to pre-B cell compartment as well as maintenance of the pre-B cell compartment. In addition, we reported that c-Myb is crucial for peripheral B cell homeostasis and that c-Myb deficient B cells are hyporesponsive to BAFF, displaying both reduced expression of BAFF-R and increased nuclear distribution of PKC-(. We have used these models to identify tentative targets of c-Myb activity that may mediate downstream c-Myb functions during B cell development. The goal of this proposal is to develop the network of crucial genes that mediate c-Myb activity during different stages of B cell development. PUBLIC HEALTH RELEVANCE: The Myb locus encodes the c-Myb protooncogene, which functions as a transcription regulator. c-Myb is absolutely required for normal hematopoiesis and is associated with a wide variety of human leukemias, lymphomas and other malignancies such as breast and colon cancer. Completion of the proposed work will clarify the role played by c-Myb during normal B cell development and identify direct targets of c-Myb activity that will provide insight into how c-Myb functions in normal hematopoiesis and cancer and identify potential therapeutic targets.